Acetaldehyde and Defective Mismatch Repair Increase Colonic Tumours in a Lynch Syndrome Model with Aldh1b1 Inactivation

Overview

Journal Dis Model Mech

Specialty General Medicine

Date 2023 Jul 3

PMID 37395714

Authors

Guia Cerretelli

Ying Zhou

Mike F Muller

David J Adams

Mark J Arends

Affiliations

Soon will be listed here.

Abstract

ALDH1B1 expressed in the intestinal epithelium metabolises acetaldehyde to acetate, protecting against acetaldehyde-induced DNA damage. MSH2 is a key component of the DNA mismatch repair (MMR) pathway involved in Lynch syndrome (LS)-associated colorectal cancers. Here, we show that defective MMR (dMMR) interacts with acetaldehyde, in a gene/environment interaction, enhancing dMMR-driven colonic tumour formation in a LS murine model of Msh2 conditional inactivation (Lgr5-CreER; Msh2flox/-, or Msh2-LS) combined with Aldh1b1 inactivation. Conditional (Aldh1b1flox/flox) or constitutive (Aldh1b1-/-) Aldh1b1 knockout alleles combined with the conditional Msh2flox/- intestinal knockout mouse model of LS (Msh2-LS) received either ethanol, which is metabolised to acetaldehyde, or water. We demonstrated that 41.7% of ethanol-treated Aldh1b1flox/flox Msh2-LS mice and 66.7% of Aldh1b1-/- Msh2-LS mice developed colonic epithelial hyperproliferation and adenoma formation, in 4.5 and 6 months, respectively, significantly greater than 0% in water-treated control mice. Significantly higher numbers of dMMR colonic crypt foci precursors and increased plasma acetaldehyde levels were observed in ethanol-treated Aldh1b1flox/flox Msh2-LS and Aldh1b1-/- Msh2-LS mice compared with those in water-treated controls. Hence, ALDH1B1 loss increases acetaldehyde levels and DNA damage that interacts with dMMR to accelerate colonic, but not small intestinal, tumour formation.

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